The identity of vascular endothelial cell derived relaxing factors has been found to be nitric oxide (hereinafter abbreviated as NO) which, like nitroglycerin used to treat angina pectoris, manifests its vascular relaxing action as mediated by the increase in cyclic GMP (hereinafter abbreviated as cGMP). Briefly, nitrites-like relaxing factors exist endogenously and counteract catecholamine and other endogenous vasoconstricting factors to adjust the tone of blood vessels to thereby contribute to the retention of adequate blood flow. Therefore, the decrease in NO or cGMP is believed to enhance vasotonia and reduce the blood flow in tissue, eventually causing circulatory disorders or ischemic heart diseases.
Increase in vasotonia resulting from damage to coronary endothelial cells which are in the class of NO producing cells is believed to induce insufficiency in the blood flow in myocardial tissue, thereby causing anginal attacks. This results from disorders in the NO-cGMP system working as an endogenous relaxing factor. The vasodilating action of nitrites depends on the diameter of blood vessels for the degree of relaxation and because of their active site specificity (i.e., thicker coronary arteries are relaxed more intensely), nitrites have so far been in common use. However, the nitrites have a disadvantage in that their action is transient and attenuated during prolonged use. In addition, it has been pointed out that among vasodilators, adenosine enhancers such as dipyridamole which dilate narrow portions of coronary arteries to increase the coronary blood flow increase the myocardial blood flow at normal sites rather than at the lesion, thereby aggravating the ischemia (this phenomenon is generally referred to as "steal") and, hence, showing side effects such as aggravation of angina pectoris and pectoralgia.
While no effective therapeutics have been available for the various pathogenic conditions that manifest pulmonary hypertension, it has recently been reported that NO gas inhalation therapy has certain utility. Since NO gas relaxes blood vessels and lower the pulmonary arterial pressure through the increase in cGMP, it is anticipated that activation of the cGMP producing system dilates selectively pulmonary arteries in the pulmonary circulation, thereby contributing to the treatment of pulmonary hypertension. Calcium blockers and many other vasodilating drugs have so far been used in attempts to treat pulmonary hypertension, none have been commercialized since every one of them is more potent in lowering the systemic blood pressure than the pulmonary arterial pressure. An oxygen therapy has been verified to be effective in achieving improvements after its application. However, oxygen intoxication occurs as a serious side effect and the occurrence of pulmonary lesions such as pulmonary edema and fibrosis has been reported with patients who were on prolonged oxygen therapy at home. The NO gas inhalation therapy is not an exception and the NO gas used in this therapy is one of the air pollutants NO.sub.x and will easily generate NO.sub.2 in the presence of oxygen, thereby potentially causing adverse effects on the airway and lungs; hence, utmost care is required in applying the NO gas and many problems are involved in its prolonged use. On the other hand, suppressing the cGMP degradation system is believed another way to maintain the concentration of cGMP, thereby allowing for selective decrease in the pulmonary arterial pressure. Briefly, an inhibitor of phosphodiesterase (hereinafter abbreviated as PDE) which is an enzyme catalyzing specific hydrolyzation of cyclic GMP holds promise as a new therapeutic free from the aforementioned side effects.
With the inhibition of PDE, cGMP increases, possibly leading to the treatment of ischemic heart diseases or pulmonary hypertension. As of today, PDE has been verified to exist in at least seven isozyme types. Of these, five types of isozymes distribute in many diverse tissues. Two isozymes are capable of selective hydrolyzation of cGMP and they are PDE type I (calmodulin-dependent PDE) and PDE type V (cGMP-PDE) On the other hand, PDE types III and IV hydrolyse cAMP selectively and PDE type II has no substrate selectivity. If the last three isozymes are inhibited, cAMP is increased to cause various obvious side effects including enhanced myocardial contraction and heart rate and depression of systemic blood pressure. Among other things, it is well known that with the inhibition of type III PDE, cAMP increases resulting in enhanced myocardial contraction. It has been reported that increased cGMP in cardiac muscle reduced myocardial contraction but the distribution of PDE type V has not been recognized in cardiac muscle. Therefore, it is anticipated that selective inhibition of PDE type V will produce selective action that is limited in the decrease in systemic blood pressure and side effects on the heart.
It has recently been found that NO releasing compounds show a inhibition of vascular smooth muscle cell proliferation with the intermediary of cGMP. For example, Garg et al. (J. Clin. Invest., 83, 1774-1777, 1989),and Nakaki et al. (Eur. J. Pharmacol., 189, 347-353, 1990) reported that the proliferation of cultured vascular smooth muscle cells isolated from aortic media in rats was suppressed by the treatment of NO releasing compounds nitroprusside, nitroglycerin, isosorbide dinitrate or 8-bromo-cGMP. Therefore, it is suggested that increased cGMP could suppress the proliferation of vascular smooth muscle cells in arteriosclerosis and post-PTCA restenosis.
The cGMP-PDE inhibitors so far disclosed in the art include pyrazolopyrimidone derivatives (see EP-A-526004), purinone derivatives (JP-A 2-88577), phenylpyrimidone derivatives (JP-A 2-295978), quinazoline derivatives (JP-A 6-192235 and JP-A 7-10843 and WO 93/12095) and phthalazine derivatives (WO 96/05176). However, there is no prior art disclosure of the fact that compounds such as the ones claimed in the present invention which have a pyridocarbazole skeleton have the cGMP-PDE inhibitory action. As for the PDE isozyme selectivity, EP-A 526004 and WO 93/12095 teach isozyme selectivity between types V and III but the selectivity has not yet been commercialized in clinical fields to demonstrate a satisfactory action.
Turning back to pyridocarbazole derivatives, their PDE inhibitory action has not yet been reported, nor are there reports that show their vasodilating action and effectiveness for pulmonary hypertension and ischemic heart diseases.
An object, therefore, of the invention is to provide novel compounds that have high isozyme selectivity and potent cGMP-PDE inhibitory action and that cause less side effects to feature high safety.
Other objects of the invention are to provide processes for producing such compounds, intermediates useful for producing them, as well as pharmaceuticals and pharmaceutical compositions containing said compounds. In particular, the invention aims at providing agents for preventing and/or treating pulmonary hypertension, ischemic heart diseases or diseases against which the cGMP-PDE inhibitory action is effective, said agents having solved at least one of the aforementioned problems with the prior art.